Calcium-dependent lectins (C-type lectins) are expressed in a large number of cell types including macrophages, B- and T-lymphocytes, mast cells, and natural killer (NK) cells. Macrophage lectin proteins perform a variety of functions in the recognition and destruction of foreign cells and pathogens. Gram positive and Gram negative bacteria have been shown to interact with C-type lectins (Athamna et al., Infect Immun 59:1673, 1991; Shimaoka et al., J. Immunol. 166(8):5108, 2001). A human macrophage C-type lectin has been found to recognize Tn Ag, a well-known human carcinoma-associated epitope (Suzuki et al., J Immunol 156:128, 1996). Furthermore, the recombinant cytosolic carbohydrate binding domain of the mouse macrophage C-type lectin also served as an inhibitor of cytotoxic activity, indicating that the lectin was a direct mediator of the macrophage tumoricidal response (Imai et al., J Immunol Methods 171:23, 1994). Unique macrophage lectins may specifically interact with surface antigens expressed by certain abnormal or diseased cells. The lectins may direct the macrophages to abnormal or diseased cells.
Conserved features of C-type lectins include an extracellular carbohydrate recognition domain (Spiess, M Biochem 29:10009, 1990). Receptor proteins of the C-type lectin superfamily do not generally share significant sequence homology beyond that of the carbohydrate recognition domain. C-type lectins are typically Type II membrane proteins. Type II membrane proteins include an extracellular C-terminus that has the carbohydrate binding domain, an amino terminal cytoplasmic domain, and a membrane-spanning domain of approximately 20 residues. Several prolines generally precede the cytoplasmic domain of the transmembrane domain. The prolines are thought to prevent steric interference of the amino-terminal domain with the transmembrane domain during membrane insertion. The N-terminal cytosolic domains of the C-type lectins are very diverse in both length and sequence. Phosphorylation of tyrosine in the cytosolic domain of the asialoglycoprotein receptor, a C-type lectin, has been demonstrated (Fallon, J Biol Chem 265:3401, 1990). The extracellular carbohydrate binding domains can be separated from membrane-bound C-type lectin molecules by protease treatment. These isolated, soluble domains retain structural integrity and carbohydrate binding activity, owing in part to the three-intrachain disulfide bonds present in the binding domains of this class of lectin.
C-type lectins play a role in the recognition and destruction of diseased and non-self cells. The selective modulation of the expression and specificity of novel C-type lectins may allow the successful management of diseases related to macrophage function, such as graft rejection or pathogen colonization, or the exploitation of the natural cytolytic capabilities of macrophages, such as specific targeting to tumors or infected host cells.
A number of groups have identified several new C-type lectins unique to macrophages and DC, such as the murine macrophage-restricted C-type lectin (mMCL) (Balch, S., et al., J. Biol. Chem. 273:18656-64, 1998); Langerin, the Langerhans cell-specific C-type lectin (Valladeau, J., Immunity 12:71-81, 2000); Mincle, a macrophage-inducible C-type lectin that is a transcriptional target of NF-IL6 in murine peritoneal macrophages (Matsumoto, M., et al., J. Immunol. 163:5039-48, 1999); DCIR, the human dendritic cell immumoreceptor, a type II glycoprotein with homology to the macrophage lectin and hepatic asialoglycoprotein receptors (Bates, E., et al., J. Immunol. 163:1973-83, 1999 and U.S. Pat. No. 6,277,959, both of which are incorporated herein by reference); and, murine Dectin-1 and Dectin-2 (DC-associated C-type lectins; Ariizumi, K., et al., J. Biol. Chem., 275:20157-167, 2000 and Ariizumi, K., et al., J. Biol. Chem., 275:11957-963, 2000, respectively), which are thought to be involved in delivering T-cell costimulatory signals.
The present invention identifies additional, novel C-type lectin polypeptides.